Triple-negative breast cancers (TNBC) have a worse prognosis and outcome relative to other breast cancer subtypes. As such, it is imperative that new molecules and pathways be identified to exploit for targeted therapy in patients with TNBC. Protein tyrosine kinase 6 (PTK6) is a soluble tyrosine kinase that is aberrantly expressed in 86% of breast cancers and absent from normal mammary epithelial cells. High expression of PTK6 in breast tumors is associated with increased metastasis and shortened overall survival. These data suggest a tumor specific role for PTK6 in breast cancer progression and make PTK6 and PTK6-induced signaling pathways attractive targets for breast cancer treatment. PTK6 is activated downstream of a diverse group of growth factor receptors, including Her2/neu, EGFR, and MET receptors. In this context of expression in mammary epithelial cells, PTK6 acts as an oncogenic node downstream of highly expressed growth factor receptors, and functions to propagate oncogenic signaling events resulting in enhanced migratory ability. Mechanisms through which PTK6 expression is acquired in breast cancer cells are largely unknown and it is still unclear how PTK6 integrates with intracellular signaling pathways. Our goal is to define the mechanisms of aberrant PTK6 expression in TNBC and to understand the function of PTK6 in the tumorigenesis and progression of aggressive, basal-type mammary tumors. To address these questions, this proposal will focus on understanding the cross-talk between factors responsible for induction of PTK6 expression, including the hypoxia-inducible factor (HIF) transcription factors and the stress steroid hormone receptor, the glucocorticoid receptor (GR). Our preliminary data suggest that HIFs and GR cooperate to induce PTK6 expression in TNBC, to ultimately allow the cancer cells to adapt to both physiologic cell stress and stress hormone signaling. Moreover, we will determine the role of mouse PTK6 (Sik) in driving basal-type mammary tumorigenesis via a transgenic mouse model in which Sik knockout (KO) mice are crossed to METmut mice with constitutively active MET receptor signaling. The resulting Sik-KO/METmut mice will allow us to assess changes in tumor number, latency, grade and metastasis when Sik is not present. These studies will provide novel insight in the regulation of PTK6 expression in breast cancer and the subsequent function of PTK6 signaling as an oncogenic driver in TNBC downstream of growth factor receptors.